Single anticodon-edited tRNA therapy targeting highly prevalent Arg>Ter premature termination codons causing inherited retinal diseases
Sarma, A. S.; Saleh, A.; Eintracht, J.; Kamal, H.; Khetab, S.; Salameh, M.; Matsevich, C.; Obolensky, A.; Banin, E.; Sharon, D.
Show abstract
Nonsense variants cause 18% of inherited retinal diseases (IRDs), yet current therapies require variant-specific development, leaving most patients untreated. Here, we combined a large-scale genetic analysis literature survey of >37,500 IRD patients with anticodon-edited (ACE)-tRNA engineering to create a single, gene-agnostic therapy targeting Arg>Ter nonsense variants which are the most prevalent subclass (35%) of premature stop codons (PTCs). We developed an optimized ACE-tRNA (V3) that achieved up to 86% readthrough across 13 clinically relevant variants, restored native PRCD localization in the arRP-causing p.R22* mutant, and demonstrated activity in photoreceptor-like cells. To enable translation, we established an AAV2/7m8 production platform (1*10{superscript 1}{superscript 2}-1*10{superscript 1}3 GC/mL) and defined 1*10 GC/eye as the safe dose in mice. This patient genetics-guided strategy positions ACE-tRNA_V3 as a promising candidate for preclinical development, offering a precision medicine approach that targets the most common nonsense variant class with a single therapeutic molecule.
Matching journals
The top 2 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- A novel multiplex RNAi therapy simultaneously targets Hif1a and Hif2a to defy retinal degeneration in two models of AMD 95%
- A Compact Base Editor Rescues AATD-associated Liver and Lung Disease in Mouse Models 95%
- Dual CRALBP isoforms unveiled: iPSC-derived retinal modelling and AAV2/5-RLBP1 gene transfer raise considerations for effective therapy 95%
Similar papers in this journal
- A high-fidelity CRISPR-Cas13 system improves abnormalities associated with C9ORF72-linked ALS/FTD 96%
- CRISPR/Cas9-Mediated Excision of ALS/FTD-Causing Hexanucleotide Repeat Expansion in C9ORF72 rescues major disease mechanisms in vivo and in vitro 96%
- Improved prime editors enable pathogenic allele correction and cancer modelling in adult mice 95%
Similar papers in this journal
- Optimizing AAV2/6 microglial targeting identified enhanced efficiency in the photoreceptor degenerative environment 95%
- AAV-mediated gene augmentation therapy restores critical functions in mutant iPSC-derived PRPF31+/- cells. 95%
- Epigenetic control of multiple genes with a single lentiviral vector encoding transcriptional repressors fused to compact zinc finger arrays 94%
Similar papers in this journal
- SAICAr-dependent and independent effects of ADSL deficiency on neurodevelopment 95%
- Retinoic acid signaling mediates peripheral cone photoreceptor survival in a mouse model of retina degeneration 95%
- Whole brain delivery of an instability-prone Mecp2 transgene improves behavioral and molecular pathological defects in mouse models of Rett syndrome 95%
Similar papers in this journal
- In vivo base editing rescues photoreceptors in a mouse model of retinitis pigmentosa 95%
- Allele-specific CRISPR/Cas9 editing inactivates a single nucleotide variant associated with collagen VI muscular dystrophy 95%
- Non-uniform dystrophin re-expression after CRISPR-mediated exon excision in the dystrophin/utrophin double-knockout mouse model of DMD 94%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.